Interleukin-1 Receptor Type 1 Inhibition Improves Blood Pressure, Fetal Growth and Immune Balance in Placental Ischemic Rats

Preeclampsia, new-onset hypertension with proteinuria or end-organ dysfunction after 20 weeks gestation, is associated with placental ischemia, maternal endothelial dysfunction, and chronic inflammation. Preeclamptic women and the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia have higher placental expression and activation of NLRP3 inflammasome and its associated cytokine, Interleukin 1β (IL-1β). We hypothesized that higher IL-1β signaling through the IL-1 receptor type 1 (IL-1R1), contributes to maternal hypertension, fetal growth restriction (FGR), and endothelial dysfunction in response to placental ischemia. GD14 timed-pregnant SD rats underwent RUPP or sham surgery with implantation of minipumps infusing IgG or IL-1R1 neutralizing antibody (αIL-1R1; 2ug/kg/day). On GD19, MAP, fetal and placental weights, blood, and tissues were collected. Plasma IL-1β was higher in RUPP vs Sham IgG controls (8.79±2.01 vs 3.24±1.05 pg/mL; p<0.01) and normalized in RUPP+αIL-1R1 (1.23±0.51 pg/mL;p<0.01 vs RUPP+IgG). MAP higher at 120±4mmHg in RUPP+IgG from 100±3mmHg in Sham+IgG (p<0.01). αIL-R1 treatment reduced MAP to 106±12 mmHg in RUPP (p<0.01 vs. RUPP+IgG). RUPP+IgG placenta weight (0.46±0.1g) was lower than Sham+IgG (0.54±0.1g; p<0.01) and significantly higher in Rupp+αIL-R1 (0.52±0.02g; p<0.05 vs RUPP+IgG). Fetal weight was higher in RUPP+αIL-1R1 (2.77±0.22 g) vs control RUPP (1.97±0.11g; p<0.01). Placental cNK, T H 17s, and macrophages were higher, and T Reg s were lower in RUPP+IgG vs Sham, and were normalized in RUPP+αIL-1R1 (p<0.05). IL-1R1 inhibition decreased IL-1R1 expression but did not reverse RUPP-induced changes in NFκB, pre-proendothelin, or eNOS expression. IL-R1 activation contributes to maternal hypertension and FGR via mediating immune populations during ischemia.